Federal Register / Vol. 72, No. 35 / Thursday, February 22, 2007 / Proposed Rules 7945 

the individual ingredients differ, the 

directions for the combination product 

may not contain any dosage that 

exceeds those established for any 

individual ingredient in the applicable 

OTC drug monograph(s), and may not 

provide for use by any age group lower 

than the highest minimum age limit 

established for any individual 

ingredient.’’

Concerns about effectiveness also 

stem from a study (Ref. 8) indicating 

that separate application of sunscreen 

followed by DEET resulted in a decrease 

in sun protection factor (SPF) after 

application of the insect repellent. Thus, 

FDA is soliciting comment on the 

following questions: 

1. Is there additional evidence 

suggesting that application of a 

sunscreen product followed by 

application of a separate insect repellent 

product results in a decrease in the 

sunscreen’s SPF? Is there evidence 

suggesting that sequential application of 

the products has no adverse effect on 

the sunscreen? 

2. Is there evidence suggesting that 

combining a sunscreen and insect 

repellent in a single formulation 

adversely impacts the effectiveness of 

the sunscreen? Is there evidence 

suggesting that such a combination has 

no adverse impact on the sunscreen 

component? 

3. Are there effective concentrations 

of the insect repellent ingredients that 

could be used to allow for liberal 

application and frequent reapplication 

of the insect repellent-sunscreen drug 

products, as directed by the sunscreen 

directions, without jeopardizing the 

safety of the consumer? How does this 

vary by insect repellent ingredient? 

Would any of the insect repellent 

ingredients be effective at such 

concentrations? 

4. Is there information available to 

show whether there are any chemical or 

physical incompatibilities between 

insect repellent and sunscreen active 

ingredients when used in combination 

products or when used separately? Are 

there any sunscreen ingredients that 

should not be used with a specific 

insect repellent ingredient? 

5. If an insect repellent ingredient 

(e.g., DEET) is labeled for 6-hour 

intervals between applications, can the 

effectiveness of the sunscreen be 

assured if the product cannot be applied 

more often than every 6 hours? Is there 

a need for a minimal SPF to assure the 

effectiveness of the combination 

product considering the wide variation 

in minimal erythemal dose (MED) 

between individuals and the need for 

reapplication due to physical stress 

such as toweling or rubbing of the skin? 

If the answer is yes, what minimal SPF 

value should be required, and what is 

the basis for that SPF value? 

6. Is there information available to 

demonstrate that there are product 

performance benefits [other than the 

convenience of using one product 

instead of two] derived from the 

concurrent application of the insect 

repellent and the sunscreen (as opposed 

to sequential application of these 

products separately)? Please submit any 

data that you reference. 

7. Oil of Citronella products are 

labeled to repeat applications at 1 hour 

intervals for maximum repellent 

effectiveness. Is it possible that insect 

repellent-sunscreen drug products can 

be formulated in such a way that the 

insect repellent reapplication intervals 

coincide more closely with the 

sunscreen reapplication intervals? Can 

this be done without jeopardizing the 

safety or effectiveness of these products? 

III. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments on this document. Three 

copies of all written comments are to be 

submitted. Individuals submitting 

written comments or anyone submitting 

electronic comments may submit one 

copy. Comments are to be identified 

with the docket number found in 

brackets in the heading of this 

document and may be accompanied by 

a supporting memorandum or brief. 

Received comments may be seen in the 

Division of Dockets Management 

between 9 a.m. and 4 p.m., Monday 

through Friday. 

IV. References 

The following references are on 

display in the Division of Dockets 

Management (see ADDRESSES) and may 

be seen by interested persons between 9 

a.m. and 4 p.m., Monday through 

Friday. 

1. EPA Reregistration Eligibility Decision 

for DEET, 1998. 

2. EPA Reregistration Eligibility Decision 

for Oil of Citronella, 1997. 

3. EPA Biopesticide Registration Eligibility 

Document for IR3535, 1999. 

4. EPA Biopesticide Registration Eligibility 

Document for p-menthane-3,8-diol, 2000. 

5. EPA Decision Memorandum on KBR 

3023, 2000. 

6. Ross, E. A. et al., ‘‘Insect Repellent 

Interactions: Sunscreens Enhance DEET 

(N,N-Diethyl-M-Toluamide) Absorption,’’

Drug Metabolism and Disposition, 32:783–

785, 2004. 

7. Gu, X. et al., ‘‘In Vitro Evaluation of 

Concurrent Use of Commercially Available 

Insect Repellent and Sunscreen 

Preparations,’’ British Journal of 

Dermatology, 152: 1263–1267, 2005. 

8. Montemarano, A. D. et al., ‘‘Insect 

Repellents and the Efficacy of Sunscreens,’’

The Lancet, 349:1670–1671, 1997. 

This request for information and 

comment is issued under sections 201, 

501, 502, 503, 505, 510, and 701 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 321, 351, 352, 353, 355, 360, 

and 371) and under authority of the 

Commissioner of Food and Drugs. 

Dated: December 5, 2006. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. E7–2890 Filed 2–21–07; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

[Docket No. DEA–301P] 

21 CFR Part 1308 

Schedules of Controlled Substances: 

Placement of Lisdexamfetamine into 

Schedule II 

AGENCY: Drug Enforcement 

Administration, U.S. Department of 

Justice. 

ACTION: Notice of proposed rulemaking. 

SUMMARY: This proposed rule is issued 

by the Deputy Administrator of the Drug 

Enforcement Administration (DEA) to 

place the substance lisdexamfetamine, 

including its salts, isomers, and salts of 

isomers, into schedule II of the 

Controlled Substances Act (CSA). This 

proposed action is based on a 

recommendation from the Assistant 

Secretary for Health of the Department 

of Health and Human Services (DHHS) 

and on an evaluation of the relevant 

data by DEA. This scheduling of 

lisdexamfetamine in schedule II will not 

be finalized until a New Drug 

Application (NDA) for a 

lisdexamfetamine product is approved 

by the Food and Drug Administration 

(FDA). If finalized, this action would 

impose the regulatory controls and 

criminal sanctions of schedule II on 

those who handle lisdexamfetamine and 

products containing lisdexamfetamine. 

DATES: Written comments must be 

postmarked, and electronic comments 

must be sent, on or before March 26, 

2007. 

ADDRESSES: To ensure proper handling 

of comments, please reference ‘‘Docket 

No. DEA–301’’ on all written and 

electronic correspondence. Written 

comments sent via regular mail should 

be sent to the Deputy Administrator, 

Drug Enforcement Administration, 

Washington, DC 20537, Attention: DEA 


erjones on PRODPC74 with PROPOSALS
7946 Federal Register / Vol. 72, No. 35 / Thursday, February 22, 2007 / Proposed Rules 

Federal Register Representative/ODL. 

Written comments sent via express mail 

should be sent to the Deputy 

Administrator, Drug Enforcement 

Administration, Attention: DEA Federal 

Register Representative/ODL, 2401 

Jefferson-Davis Highway, Alexandria, 

VA 22301. Comments may be directly 

sent to DEA electronically by sending an 

electronic message to 

dea.diversion.policy@usdoj.gov. 

Comments may also be sent 

electronically through http:// 

www.regulations.gov using the 

electronic comment form provided on 

that site. An electronic copy of this 

document is also available at the http:// 

www.regulations.gov Web site. DEA will 

accept electronic comments containing 

MS Word, WordPerfect, Adobe PDF, or 

Excel file formats only. DEA will not 

accept any file format other than those 

specifically listed here. 

FOR FURTHER INFORMATION CONTACT: 

Christine Sannerud, PhD, Chief, Drug 

and Chemical Evaluation Section, Drug 

Enforcement Administration, 

Washington, DC 20537, (202) 307–7183. 

SUPPLEMENTARY INFORMATION: 

Lisdexamfetamine is a central nervous 

system stimulant drug. The Food and 

Drug Administration (FDA) is currently 

reviewing a New Drug Application 

(NDA) for lisdexamfetamine. Upon 

approval of this pending NDA, 

lisdexamfetamine will be marketed as a 

prescription drug product for the 

treatment of Attention Deficit 

Hyperactivity Disorder (ADHD). 

Lisdexamfetamine is an amide ester 

conjugate comprised of the amino acid 

L-lysine covalently bound to the amino 

group of d-amphetamine. The chemical 

name of its dimesylate salt form is (2S)- 

2,6-diamino-N-[(1S)-1-methyl-2- 

phenethyl]hexanamide 

dimethanesulfonate (CAS number 

608137–32–3). Lisdexamfetamine per se 

is pharmacologically inactive and its 

effects are due to its in vivo metabolic 

conversion to d-amphetamine. In this 

regard, lisdexamfetamine acts as a 

prodrug. 

Lisdexamfetamine shares substantial 

pharmacological effects and abuse 

potential with amphetamine. 

Lisdexamfetamine is positively 

reinforcing in monkeys. It generalizes to 

the discriminative stimulus effects of damphetamine in monkeys. It produces 

locomotor stimulation in rats. In adults, 

the total amphetamine exposure 

resulting from 75 mg oral 

lisdexamfetamine is equivalent to 35 mg 

oral Adderall XR, an extended release 

amphetamine product. Peak plasma 

concentrations of d-amphetamine 

following oral ingestion of 50 and 70 mg 

lisdexamfetamine correspond closely to 

those produced by oral ingestion of 30 

and 50 mg immediate-release damphetamine product. In controlled 

clinical studies, lisdexamfetamine has 

been found to be similar to damphetamine in psychoactive measures. 

It produces euphoria in humans typical 

of d-amphetamine. Lisdexamfetamine 

shows an adverse event profile similar 

to that of d-amphetamine. Some adverse 

effects of lisdexamfetamine include 

insomnia, nervousness, irritability, 

anorexia, weight loss, mood alterations, 

and increases in blood pressure and 

heart rate. 

Lisdexamfetamine has not been 

studied for its psychological and 

physical dependence potential. 

However, since lisdexamfetamine is a 

prodrug for d-amphetamine, it is 

expected to possess dependence 

potential similar to that of damphetamine. d-Amphetamine is 

known to cause both psychological and 

physical dependence. Some symptoms 

of d-amphetamine withdrawal include 

depression, increase in sleep and food 

intake, drug craving, anhedonia, 

irritability and poor concentration. 

Lisdexamfetamine is a new molecular 

entity and has not been marketed in the 

United States or other countries. 

Therefore, there has been no evidence of 

diversion, abuse, or law enforcement 

encounters involving lisdexamfetamine. 

On November 14, 2006, the Assistant 

Secretary for Health, DHHS, sent the 

Deputy Administrator of DEA a 

scientific and medical evaluation and a 

letter recommending that 

lisdexamfetamine be placed into 

schedule II of the CSA. Enclosed with 

the November 14, 2006 letter was a 

document prepared by the FDA entitled, 

‘‘Basis for the Recommendation for 

Control of Lisdexamfetamine in 

Schedule II of the Controlled Substances 

Act.’’ The document contained a review 

of the factors which the CSA requires 

the Secretary to consider (21 U.S.C. 

811(b)). 

The factors considered by the 

Assistant Secretary of Health and DEA 

with respect to lisdexamfetamine were: 

(1) Its actual or relative potential for 

abuse; 

(2) Scientific evidence of its 

pharmacological effects; 

(3) The state of current scientific 

knowledge regarding the drug; 

(4) Its history and current pattern of 

abuse; 

(5) The scope, duration, and 

significance of abuse; 

(6) What, if any, risk there is to the 

public health; 

(7) Its psychic or physiological 

dependence liability; and 

(8) Whether the substance is an 

immediate precursor of a substance 

already controlled under this 

subchapter. (21 U.S.C. 811(c)) 

Based on the recommendation of the 

Assistant Secretary for Health, received 

in accordance with section 201(b) of the 

Act (21 U.S.C. 811(b)), and the 

independent review of the available 

data by DEA, the Deputy Administrator 

of DEA, pursuant to sections 201(a) and 

201(b) of the Act (21 U.S.C. 811(a) and 

811(b)), finds that: 

(1) Lisdexamfetamine has a high 

potential for abuse; 

(2) Upon approval of the pending 

NDA, lisdexamfetamine will have a 

currently accepted medical use in 

treatment in the United States; and 

(3) Abuse of lisdexamfetamine may 

lead to severe psychological or physical 

dependence. 

Based on these findings, the Deputy 

Administrator of DEA concludes that 

lisdexamfetamine, including its salts, 

isomers, and salts of isomers, warrants 

control in schedule II of the CSA, if and 

when an NDA for lisdexamfetamine is 

approved. 

Interested persons are invited to 

submit their comments, objections or 

requests for a hearing with regard to this 

proposal. Requests for a hearing should 

state, with particularity, the issues 

concerning which the person desires to 

be heard. All correspondence regarding 

this matter should be submitted to the 

Deputy Administrator, Drug 

Enforcement Administration, 

Washington, DC, 20537, Attention: DEA 

Federal Register Representative/ODL. In 

the event that comments, objections, or 

requests for a hearing raise one or more 

issues which the Deputy Administrator 

finds warrant a hearing, the Deputy 

Administrator shall order a public 

hearing by notice in the Federal 

Register, summarizing the issues to be 

heard and setting the time for the 

hearing. 

Requirements for Handling 

Lisdexamfetamine 

If this rule is finalized as proposed, 

lisdexamfetamine would be subject to 

CSA regulatory controls and 

administrative, civil and criminal 

sanctions applicable to the manufacture, 

distribution, dispensing, importing and 

exporting of a schedule II controlled 

substance, including the following: 

Registration. Any person who 

manufactures, distributes, dispenses, 

imports, exports, engages in research or 

conducts instructional activities with 

lisdexamfetamine, or who desires to 

manufacture, distribute, dispense, 

import, export, engage in instructional 

activities or conduct research with 


erjones on PRODPC74 with PROPOSALS
Federal Register / Vol. 72, No. 35 / Thursday, February 22, 2007 / Proposed Rules 7947 

lisdexamfetamine, would be required to 

be registered to conduct such activities 

in accordance with Part 1301 of Title 21 

of the Code of Federal Regulations. 

Security. Lisdexamfetamine would be 

subject to schedule II security 

requirements and must be 

manufactured, distributed and stored in 

accordance with §§ 1301.71, 1301.72(a), 

(c), and (d), 1301.73, 1301.74, 

1301.75(b) and (c), 1301.76 and 1301.77 

of Title 21 of the Code of Federal 

Regulations. 

Labeling and Packaging. All labels 

and labeling for commercial containers 

of lisdexamfetamine which are 

distributed after finalization of this rule 

would be required to comply with 

requirements of §§ 1302.03–1302.07 of 

Title 21 of the Code of Federal 

Regulations. 

Quotas. Quotas for lisdexamfetamine 

would be established pursuant to part 

1303 of Title 21 of the Code of Federal 

Regulations. 

Inventory. Every registrant required to 

keep records and who possesses any 

quantity of lisdexamfetamine would be 

required to keep an inventory of all 

stocks of lisdexamfetamine on hand 

pursuant to §§ 1304.03, 1304.04 and 

1304.11 of Title 21 of the Code of 

Federal Regulations. Every registrant 

who desires registration in schedule II 

for lisdexamfetamine would be required 

to conduct an inventory of all stocks of 

the substance on hand at the time of 

registration. 

Records. All registrants would be 

required to keep records pursuant to 

§§ 1304.03, 1304.04, 1304.21, 1304.22, 

and 1304.23 of Title 21 of the Code of 

Federal Regulations. 

Reports. All registrants required to 

submit reports to the Automation of 

Reports and Consolidated Order System 

(ARCOS) in accordance with § 1304.33 

of Title 21 of the Code of Federal 

Regulations would be required to do so 

for lisdexamfetamine. 

Orders for Lisdexamfetamine. All 

registrants involved in the distribution 

of lisdexamfetamine would be required 

to comply with the order form 

requirements of part 1305 of Title 21 of 

the Code of Federal Regulations. 

Prescriptions. All prescriptions for 

lisdexamfetamine or prescriptions for 

products containing lisdexamfetamine 

would be required to be issued pursuant 

to 21 CFR 1306.03–1306.06 and 

1306.11–1306.15. 

Importation and Exportation. All 

importation and exportation of 

lisdexamfetamine would need to be in 

compliance with part 1312 of Title 21 of 

the Code of Federal Regulations. 

Criminal Liability. Any activity with 

lisdexamfetamine not authorized by, or 

in violation of, the Controlled 

Substances Act or the Controlled 

Substances Import and Export Act 

occurring on or after finalization of this 

proposed rule would be unlawful. 

Regulatory Certifications 

Executive Order 12866 

In accordance with the provisions of 

the CSA (21 U.S.C. 811(a)), this action 

is a formal rulemaking ‘‘on the record 

after opportunity for a hearing.’’ Such 

proceedings are conducted pursuant to 

the provisions of 5 U.S.C. 556 and 557 

and, as such, are exempt from review by 

the Office of Management and Budget 

pursuant to Executive Order 12866, 

section 3(d)(1). 

Regulatory Flexibility Act 

The Deputy Administrator, in 

accordance with the Regulatory 

Flexibility Act (5 U.S.C. 605(b)), has 

reviewed this proposed rule and by 

approving it certifies that it will not 

have a significant economic impact on 

a substantial number of small entities. 

Lisdexamfetamine products will be 

prescription drugs used for the 

treatment of Attention Deficit 

Hyperactivity Disorder (ADHD). 

Handlers of lisdexamfetamine will also 

handle other controlled substances used 

to treat ADHD which are already subject 

to the regulatory requirements of the 

CSA. 

Executive Order 12988 

This regulation meets the applicable 

standards set forth in Sections 3(a) and 

3(b)(2) of Executive Order 12988 Civil 

Justice Reform. 

Executive Order 13132 

This rulemaking does not preempt or 

modify any provision of state law; nor 

does it impose enforcement 

responsibilities on any state; nor does it 

diminish the power of any state to 

enforce its own laws. Accordingly, this 

rulemaking does not have federalism 

implications warranting the application 

of Executive Order 13132. 

Unfunded Mandates Reform Act of 

1995 

This rule will not result in the 

expenditure by state, local and tribal 

governments, in the aggregate, or by the 

private sector, of $118,000,000 or more 

in any one year, and will not 

significantly or uniquely affect small 

governments. Therefore, no actions were 

deemed necessary under provisions of 

the Unfunded Mandates Reform Act of 

1995. 

Congressional Review Act 

This rule is not a major rule as 

defined by § 804 of the Small Business 

Regulatory Enforcement Fairness Act of 

1996 (Congressional Review Act). This 

rule will not result in an annual effect 

on the economy of $100,000,000 or 

more; a major increase in costs or prices; 

or significant adverse effects on 

competition, employment, investment, 

productivity, innovation, or on the 

ability of United States-based 

companies to compete with foreign 

based companies in domestic and 

export markets. 

List of Subjects in 21 CFR Part 1308 

Administrative practice and 

procedure, Drug traffic control, 

Narcotics, Prescription drugs. 

Under the authority vested in the 

Attorney General by section 201(a) of 

the CSA (21 U.S.C. 811(a)), and 

delegated to the Administrator of DEA 

by U.S. Department of Justice 

regulations (28 CFR 0.100), and 

redelegated to the Deputy Administrator 

pursuant to 28 CFR 0.104, the Deputy 

Administrator hereby proposes that 21 

CFR part 1308 be amended as follows: 

PART 1308—SCHEDULES OF 

CONTROLLED SUBSTANCES 

[AMENDED] 

1. The authority citation for 21 CFR 

part 1308 continues to read as follows: 

Authority: 21 U.S.C. 811, 812, 871(b) 

unless otherwise noted. 

2. Section 1308.12 is proposed to be 

amended by adding a new paragraph 

(d)(5) to read as follows: 

§ 1308.12 Schedule II. 

* * * * * 

(d) * * * 

(5) Lisdexamfetamine, its salts, 

isomers, and salts of its isomers 1205 

* * * * * 

Dated: February 12, 2007. 

Michele M. Leonhart, 

Deputy Administrator. 

[FR Doc. E7–2993 Filed 2–21–07; 8:45 am] 

BILLING CODE 4410–09–P 


erjones on PRODPC74 with PROPOSALS